Core 2 GlcNAc-T inhibitors III

ABSTRACT

A method of treating a subject in need of therapy for a condition involving detrimental activity of the enzyme core 2 GlcNAc-T is provided, comprising administration of a therapeutically effective amount of an inhibitor of core 2 GlcNAc-T of the formula I to a patient in need thereof 
     
       
         
         
             
             
         
       
     
     wherein 
     R 1  is H, —OH, C 1-6  alkoxy, —NR 5 R 6 , or Sac 1; 
     R 2  is H, —OH, C 1-6  alkoxy or Sac 2; 
     R 3  is H, —OH, C 1-6  alkoxy or Sac 3; 
     R 4  is H, C 1-6  alkyl, C 1-6  hydroxyalkyl or C 1-6 -alkoxy-C 1-6 -alkyl; 
     R 5  is H, C 1-6  alkyl or C 1-6  acyl; 
     R 6  is H, C 1-6  alkyl or C 1-6  acyl; 
     Sac 1 Sac 2 and Sac 3 are independently selected saccharide moieties; and 
     Z is a steroid moiety; 
     or a pharmaceutically acceptable salt, ether or ester form thereof

The present invention relates to the use of known and novel compounds aspharmaceutical actives against diseases susceptible to treatment bymodulation, eg. inhibition, of the enzyme Core 2 GlcNAc-transferase (EC2.4.1.162), also known as UDP-GlcNAc:Galβ1,3GalNAc-R (GlcNAc to GalNAc)β-1,6-N-acetylglucosaminyl transferase (core 2β-1,6N-acetylaminotransferase, hereinafter referred to as Core 2 GlcNAc-T.

Inhibitors of Core 2 GlcNAc-T, and the present compounds in particular,have application in therapy for diseases in which core 2 GlcNAc-T isimplicated and especially those in which the enzyme activity is raisedrelative to the normal level in the tissue type concerned, or thoseconditions in which it is advantageous to lower the activity of core 2GlcNAc-T for example to its normal level or below. Examples of suchconditions are inflammatory diseases such as atherosclerosis andmultiple sclerosis, diabetes, cancer and its metastasis.

Inhibitors of Core 2 GlcNAc-T are known but none are in clinicaldevelopment as isolated actives for pharmaceutical use. Examples ofknown compounds are disclosed in WO0187548, Kuhns (15), Hindsgaul (45)and Toki (46).

Applicant's co-pending application WOO5060977 (incorporated herein byreference) discloses known and novel steroidal glycosides that havetherapeutic use as Core GlcNAc-T inhibitors, discusses the basis for useof such inhibitors in therapy and discloses published documentsdetailing the basis for Core 2 GlcNAc-T involvement in a number ofdiseases. The present application discloses further steroidal glycosidecompounds that are suitable for use in therapy for diseases in whichCore 2 GlcNAc-T is implicated and additional such conditions in whichsuch compounds have a therapeutic use.

Some of the presently disclosed steroidal glycosides have been testedpreviously in a limited number of disease paradigms. For example inprotection against gastric mucosal lesions in rats (80), in mouse earedema tests for anti inflammatory activity (79), in treatment ofdementia (U.S. Pat. No. 6,593,301) as “immuno-modulators” andspermatogenesis and ovulation stimulators (74) and as adjuvants (75).Compounds of the invention have also been used in cytotoxicity assays(e.g. 36, 40, 72), however cytotoxic concentrations are several ordersof magnitude higher than those currently disclosed for inhibition ofCore 2 GlcNAc-T activity. None of the aforementioned publicationsdiscloses that certain steroidal glycosides are inhibitors of Core 2GlcNAc-T.

Certain plant sterol compounds, some of which are used as dietarysupplements, impede the uptake of cholesterol from the gut andconsequently lower plasma LDL cholesterol. However these compounds aregenerally used in doses of several grams per day and are not known to beinhibitors of Core 2 GlcNAc-T.

In a first aspect the present invention is provided a method of treatinga subject in need of therapy for a condition involving detrimentalactivity of the enzyme core 2 GlcNAc-T, particularly raised activity,comprising administration of a therapeutically effective amount of aninhibitor of core 2 GlcNAc-T of formula I to a patient in need thereof

wherein

R¹ is H, —OH, C₁₋₆ alkoxy, —NR⁵R⁶, or Sac 1;

R² is H, —OH, C₁₋₆ alkoxy or Sac 2;

R³ is H, —OH, C₁₋₆ alkoxy or Sac 3;

R⁴ is H, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl or C₁₋₆-alkoxy-C₁₋₆-alkyl;

R⁵ is H, C₁₋₆ alkyl or C₁₋₆ acyl;

R⁶ is H, C₁₋₆ alkyl or C₁₋₆ acyl;

Sac 1, Sac 2 and Sac 3 are independently selected saccharide moietiesattached to the ring through an oxygen; and

Z is a steroid moiety;

or a pharmaceutically acceptable salt, ether, ester or tautomeric formthereof.

When one of R¹ to R³ is a saccharide moiety, the ring of formula I isdesignated ring A.

R¹ is H, —OH, C₁₋₆ alkoxy, —NR⁵R⁶, or Sac 1; preferably R¹ is H, —OH, orSac 1; more preferably R¹ is Sac 1;

R² is H, —OH, C₁₋₆ alkoxy or Sac 2; preferably R² is H, —OH or Sac 2;more preferably R²is —OH;

R³ is H, —OH, C₁₋₆ alkoxy or Sac 3; preferably R³ is H, —OH or Sac 3;more preferably R³ is Sac 3;

R⁴ is H, C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl or C₁₋₆-alkoxy-C₁₋₆-alkyl;preferably R⁴ is H, C₁₋₆ alkyl or C₁₋₆ hydroxyalkyl; more preferably R⁴is H, —CH₂OH or —CH₃; more preferably still R⁴ is —CH₂OH; morepreferably still R⁴ is —CH₂OH and the resultant moiety is a glucose orgalactose moiety; most preferably R⁴ is —CH₂OH and the resultant moietyis a glucose moiety;

R⁵ is H, C₁₋₆ alkyl or C₁₋₆ -acyl; preferably R⁵ is H or C₁₋₆ alkyl;more preferably R⁵ is H or —CH₃; most preferably R⁵is H;

R⁶ is H, C₁₋₆ alkyl or C₁₋₆ acyl; preferably R⁶ is H—CH₃ or —COCH₃; mostpreferably R⁶ is —COCH₃; and

Sac 1, Sac 2 and Sac 3 are saccharide moieties attached to the ringthrough an oxygen; preferably Sac 1 Sac 2 and Sac 3 are independentlyselected from monosaccharide moieties and disaccharide moieties;preferably they are monosaccharide moieties; more preferably Sac 1 Sac 2and Sac 3 are independently selected from a tetrose a pentose and ahexose. Preferably Sac 1 is selected from a pentose, a deoxy-aldohexoseand an aldohexose; more preferably Sac 1 is selected from arabinose,xylose, glucose, mannose, galactose, and a deoxy-aldohexose; morepreferably Sac 1 is selected from arabinose, xylose, glucose, mannose,galactose, and a 6-deoxyaldohexose; more preferably Sac 1 is selectedfrom glucose, galactose, arabinose, xylose and rhamnose; most preferablyit is rhamnose;

Preferably Sac 2 is selected from a pentose, a deoxy-aldohexose and analdohexose; more preferably Sac 2 is selected from arabinose, xylose,glucose, mannose, galactose, and a deoxyaldohexose; more preferably Sac2 is selected from arabinose, xylose, glucose, mannose, galactose, and a6-deoxyaldohexose; more preferably Sac 2 is selected from. glucose,galactose, arabinose, xylose and rhamnose;

Preferably Sac 3 is selected from a pentose, a deoxy aldohexose and analdohexose; arabinose, xylose, quinovose rhamnose or an aldohexose, morepreferably Sac 3 is selected from arabinose, xylose, quinovose,rhamnose, mannose, glucose and galactose, most preferably Sac 3 isrhamnose or glucose;

Z is a steroid moiety;

or a pharmaceutically acceptable salt, ether, ester or tautomeric formthereof.

The present inventors have determined that because of its involvement inthe synthesis of particular branched oligosaccharides, Core 2 GlcNAc-Tmodulation, particularly inhibition, may be used to treat inter alia,vascular diseases, (including complications of diabetes), autoimmune andinflammatory conditions. Particular conditions subject to treatment bythe present invention are myopathy, retinopathy, nephropathy,atherosclerosis, asthma, rheumatoid arthritis, inflammatory boweldisease, transplant rejection, ischemia reperfusion injury (e.g. stroke,myocardial ischemia, intestinal reperfusion e.g. after hemorrhagicshock,), restenosis, ileitis, Crohn's disease, thrombosis, cholitisincluding for example ulcerative cholitis), lupus, frost bite injury,acute leukocyte mediated lung injury (eg adult respiratory distresssyndrome), traumatic shock, septic shock, nephritis, psoriasis,cholicytitis, cirrhosis, diverticulitis, fulminant hepatitis, gastritis,gastric and duodenal ulcers, hepatorenal syndrome, irritable bowelsyndrome, jaundice, pancreatitis, ulcerative cholitis, human granulocyteehlichiosis, Wiskott-Aldrich syndrome T-cell activation, AIDS, infectionwith viruses, bacteria, protozoa and parasites adapted to use particularcore 2 derived glycans and cancer. Cancer metastasis is a particularlytreatable by the present method (see references 1-15, 47-57, 67-70, 81and 82 for evidence of the association of Core 2 GlcNAc-T or glycansformed by Core 2 GlcNAc-T with these diseases).

Cancers may include, for example, leukemias, lymphomas, melanomas,adenomas, sarcomas, and carcinomas of solid tissues; particularlycancers include prostate, testicular, mammary, pancreatic, cervical,uterine, kidney, lung, rectum, breast, gastric, thyroid, neck, cervix,bowel, salivary gland, bile duct, pelvis, mediastinum, urethra,bronchogenic, bladder, esophagus, colon, small intestine and sarcomas(eg. Kaposi's sarcoma) and adenomatous polyps. Particularly susceptiblecancers for treatment are oral cavity carcinomas, pulmonary cancers suchas pulmonary adenocarcinoma, colorectal cancer, bladder carcinoma, livertumours, stomach tumours colon tumours, prostate cancer, testiculartumour, mammary cancer, lung tumours oral cavity carcinomas. Particularapplication is found in cancer or its metastasis where Core 2 GlcNAc-Tactivity is raised.

Preferably the compound of the formula I is a compound of the formula II

wherein

R² is H, —OH, or C₁₋₆ alkoxy; more preferably R² is H or —OH, R⁴ is asdefined above; and Sac 1 and Sac 3 are saccharide moieties.

More preferred compounds are those of the formula II wherein R⁴ is H,—CH₂OH or —CH₃;

Particularly preferred still are those compounds wherein: R₄ is —CH₂OH;

More preferred still are those compounds wherein: R₄ is —CH₂OH and themoiety A is a glucose moiety;

In a preferred combination Ring A is either glucose or galactose;preferably glucose; Sac 1 is selected from glucose, galactose,arabinose, xylose and rhamnose and is preferably rhamnose; Sac 3 isselected from glucose, galactose, arabinose, xylose and rhamnose;preferably glucose.

Most preferred are compounds of the formula I which are of the formulaIII:

Wherein the ring A is a glucose moiety, and which formula may be written

In which Rha represents rhamnose, Glc represents glucose and 2 and 4 arethe positions of ring A to which the saccharides are attached.

Most preferred are compounds which are6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranosidesof steroid moieties Z.

Alternatively compounds of the formula I are compounds of the formulaIV:

wherein:

wherein R¹ is H, —OH, C₁₋₆ alkoxy, —NR⁵R⁶, or Sac 1; preferably R¹ is—OH, C₁₋₆ alkoxy or —NR⁵R⁶; more preferably R¹ is —NR⁵R⁶

R³ is H, —OH or C₁₋₆ alkoxy; preferably R³ is H or —OH

R⁴ and Sac 2 are as defined above;

Preferred compounds of the formula IV are compounds in which:

R¹ is —OH, C₁₋₆ alkoxy or NR⁵R⁶; R⁴ is H, C₁₋₆ alkyl or C₁₋₆hydroxyalkyl; Sac 2 is glucose, galactose, arabinose, xylose andrhamnose

More preferred compounds of the formula IV are those in which: R¹ is—NH—C₁₋₆-acyl; R⁴ is —CH₃ or —CH₂OH; Most preferred are the compounds ofthe formula IV which are of the formula Galβ1→3(6-deoxy)GalNAcα-Z

The term “steroid moiety” denotes a moiety comprising a tetracyclic ringsystem shown as formula V:

Typically the steroid moiety ring system is modified, for example by theaddition of one or more further rings and/or one or more double bondsand/or one or more substituents. Typically the saccharide ring A isattached to the steroid moiety at the 3 position. The steroid moiety mayfor example have the ring system of cholestane, pregnane, androstane,estrane, cholesterol, cholane, progestin, a mineralocorticoid, such asdehydroepiandrosterone or its 7-keto or 7-hydroxy analogue or a bileacid.

In one preferred embodiment the steroid moiety is that of a steroid thatis in itself beneficial or neutral. By neutral is meant that the steroidring is that which is considered suitable, whether as approved eg. bythe FDA or as GRAS, for use in a human or animal. By beneficial is meantthat the steroid has effects of benefit to the human or animal if itwere administered separately.

The steroid moiety Z may for example be that of a steroidal sapogeninderivable from natural sources (for example plant sources) or asteroidal moiety which is itself derivable from such steroidalsapogenins by chemical modification. The sapogenin may for example bethat of a furostanol glycoside, a spirostanol glycoside (including thosewith nitrogen and oxygen containing rings) a damarane glycoside or othersteroidal saponin. The steroid moiety Z for example may be a steroidmoiety of the formula VI

Groups or rings that may be incorporated into the steroid core V or VIare selected from those set out in formulae VI a to VI e wherein thedotted lines represent the relevant rings of the steroid core.

wherein:

R⁷, R¹⁴, R²² and R²⁴ are independently selected from H and —OH;

R⁸, R¹⁸, R²³, R²⁷ R²⁹ and R³³ are independently selected from C₁₋₆alkyl; preferably R⁸, R¹⁸, R²³, R²⁷, R²⁹ and R³³ are —CH₃;

R⁹, R¹¹ and R¹⁶ are independently selected from H and C₁₋₆ alkyl;preferably R⁹, R¹¹ and R¹⁶ are independently selected from H and —CH₃;

R¹⁰ is H or —OH or the H normally also present is absent and R¹⁰ is ═O;

R¹² is H, —OH or C₁₋₆ acyl or a group selected from VII a or VII b;preferably R¹² is H, —OH or acetyl or a group selected from VII a or VIIb;

R¹³ is H.

R¹⁵ is H, C₁₋₆ alkyl or —OH or R¹³ and R¹⁵ taken together form a—CH₂—CH₂— group; preferably R¹⁵ is H, —OH or —CH₃ or R¹³ and R¹⁵ takentogether form a —CH₂—CH₂— group;

R¹⁷ is H, C₁₋₆ alkyl or C₁₋₆ hydroxyalkyl; preferably R¹⁷ is H, —CH₂OH,or —CH₃.

R¹⁹ is H or —OH.

R²⁰ is H, —OH or C₁₋₆ alkoxy or R¹⁹ and R²⁰ taken together represent thesecond bond of a double bond joining adjacent carbon atoms; preferablyR²⁰ is H, —OH or —OCH₃ or R¹⁹ and R²⁰ taken together represent thesecond bond of a double bond joining adjacent carbon atoms.

R²¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or a C₁₋₆ alkyl or C₂₋₆alkenyl group substituted by one or more groups selected from the groupconsisting of —OH, C₁₋₆ alkoxy and Sac 4; preferably R²¹ is C₂₋₆alkenyl, or a C₁₋₆ alkyl or C₂₋₆ alkenyl group substituted by one ormore groups selected from the group consisting of —OH, C₁₋₆ alkoxy andSac 4; more preferably R²¹ is C₂₋₆ alkenyl or a C₁₋₆ alkyl or C₂₋₆alkenyl group substituted by one or more groups selected from the groupconsisting of —OH, —OCH₃ and Sac 4; most preferably R²¹ is selected fromthe group consisting of 3-methylenbutyl substituted at the 4-position bySac4, 4-hydroxy-3-methybutanyl, 3-methyl but-2-eneyl,2-methyl-prop-2-enyl, 3-methylbutanyl substituted at the 4-position bySac4, 1-hydroxy-3-methylbutanyl substituted at the 4-position by Sac4 or1-methoxy-3-methylbutanyl substituted at the 4-position by Sac4,

R²⁵ is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl or ═CH₂; preferably R²⁵ is —CH₃,—CH₂OH or ═CH₂;

R²⁶ is —OH;

R²⁸ is C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; preferably R²⁸ is C₂₋₆alkenyl; most preferably it is 2-methylprop-2-enyl

R³⁰ is C₁₋₆ hydroxyalkyl;

R³¹ is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl or C₁₋₆ alkyl substituted by Sac 5;preferably R³¹ is C₁₋₆ alkyl or C₁₋₆ alkyl substituted by Sac 5; morepreferably R³¹ is —CH₃ or —CH₂-Sac 5.

R³² is C₁₋₈ alkyl, C₂₋₈ alkenyl or C₂₋₈ alkynyl; preferably R³² is C₁₋₈alkyl or C₂₋₈ alkenyl; more preferably 3-ethyl-4-methyl-pentanyl or5-methyl-hex-4-enyl;

R³⁴ is C₁₋₆ hydroxyalkyl or C₁₋₆ alkyl substituted by Sac 6; preferablyR³⁴ is C₁₋₆ alkyl substituted by Sac 6; more preferably R³⁴ is —CH₂-Sac6;

R³⁵ is C₁₋₆ alkyl; preferably R³⁵ is —CH₃; and

Sac 4, Sac 5 and Sac 6 are independently selected saccharides;preferably Sac 4, Sac5 and Sac 6 are independently selectedmonosaccharides; more preferably they are independently selected ahexose, a pentose or a tetrose; more preferably still they areindependently selected from glucose, galactose, quinovose, fucose,arabinose and xylose, most preferably they are glucose.

Represents a bond that is either double or single; and

X is either O or NH; preferably X is O.

Preferred steroid moieties Z that do not incorporate further groupsVI(a) to VI(e) are those in which R⁹ is C₁₋₆ alkyl; R¹¹ is H; and R¹² isVII(a); preferably R⁹ is C₁₋₆ alkyl; R¹¹ is H; R¹² is VII(a); R¹⁵ isC₁₋₆ alkyl and R¹⁰ is H or —OH; more preferably R⁹ is C₁₋₆ alkyl; R¹¹ isH; R¹² is VII(a); R¹⁵ is C₁₋₆ alkyl; R¹⁰ is H or —OH, R¹⁶ is C₁₋₆ alkyland R¹⁷ is C₁₋₆ alkyl or C₁₋₆ hydroxyalkyl.

Further preferred steroid moieties Z that do not incorporate furthergroups VI(a) to VI(e) are those in which R⁹ is C₁₋₆ alkyl; R¹¹ is H; andR¹² is VII(b); preferably R⁹ is C₁₋₆ alkyl; R¹¹ is H; R¹² is VII(b) andR¹⁶, R¹⁷ and R¹⁵ are C₁₋₆ alkyl; more preferably R⁹ is C₁₋₆ alkyl; R¹¹is H; R¹² is VII(b) and R¹⁶, R¹⁷ and R¹⁵ are C₁₋₆ alkyl and R¹⁰ is H or—OH.

Further preferred steroid moieties Z that do not incorporate furthergroups VI(a) to VI(e) are those in which R⁹ is H; R¹¹ is C₁₋₆ alkyl; andR¹² is C₁₋₆ acyl; preferably R⁹ is H; R¹¹ is C₁₋₆ alkyl; R¹² is C₁₋₆acyl; R¹⁶ and R¹⁷ are H R¹⁵ is H or —OH.

Further preferred steroid moieties Z that do not incorporate furthergroups VI(a) to VI(e) are those in which R⁹ is H; R¹¹ is C₁₋₆ alkyl; andR¹² is VII b; preferably R⁹ is H; R¹¹ is C₁₋₆ alkyl; R¹² is VIIb; R¹⁶and R¹⁷ are H; and R¹⁵ is H or —OH;

More preferred are steroid moieties Z selected from groups V whichincorporate further groups VI a, VI c, VI d and VI e.

Preferred steroid moieties Z incorporating further groups VI a are thosein which R⁹ is H, R¹¹ is C₁₋₆ alkyl; R¹² is H or —OH; R¹⁶ and R¹⁷ are Hand R²¹ is C₂₋₆ alkenyl or a C₁₋₆ alkyl or C₂₋₆ alkenyl groupsubstituted by one or more groups selected from the group consisting of—OH, —OCH₃ and Sac 4; preferably R⁸ is C₁₋₆ alkyl and R⁹ is H and R¹¹ isC₁₋₆ alkyl; R¹² is H or —OH; R¹⁶ and R¹⁷ are H and R²¹ is3-methylenbutyl substituted at the 4-position by Sac 4, 3-methylbut-2-eneyl, 2-methyl-prop-2-enyl, 4-hydroxy-3-methylbutanyl,3-methylbutanyl substituted at the 4-position by Sac4,1-hydroxy-3-methylbutanyl substituted at the 4-position by Sac4 or1-methoxy-3-methylbutanyl substituted at the 4-position by Sac 4;

Alternatively, steroid moieties Z incorporating further groups VI a arethose in which R⁹ is C₁₋₆ alkyl; R¹¹ is H; R²⁰ is H; and R²¹ is a C₂₋₆alkenyl; preferably R⁹ is C₁₋₆ alkyl; R¹¹ is H; R²⁰ is H; R²¹ is a C₂₋₆alkenyl; and R¹⁰ is H; more preferably R⁹ is C₁₋₆ alkyl; R¹¹ is H; R²⁰is H; R²¹ is a C₂₋₆ alkenyl; R¹⁰ is H; and R¹⁵ is —OH or —CH₂—CH₂—; morepreferably R⁹ is C₁₋₆ alkyl; R¹¹ is H; R²⁰ is H; R²¹ is a C₂₋₆ alkenyl;R¹⁰ is H; R¹⁵ is —OH or —CH₂—CH₂—; and R¹⁶ and R¹⁷ is C₁₋₆ alkyl.

Preferred steroid moieties Z incorporating further groups VI c are thosein which R⁸ is C₁₋₆ alkyl and R⁹ is H and R¹¹ is C₁₋₆ alkyl; R¹² is H or—OH; R¹⁵ is H or —OH; R¹⁶ and R¹⁷ are H; more preferred steroid moietiesZ incorporating further groups VI c are those in which R⁸ is C₁₋₆ alkyland R⁹ is H and R¹¹ is C₁₋₆ alkyl; R¹² is H or —OH; R¹⁵ is H or —OH; R¹⁶and R¹⁷ are H and X is O.

Preferred steroid moieties of formula VI a and VI b are those having thering structures below: still more preferably having the substitutions asset forth therein.

In each case the chiral centre at the carbon labelled “25” can be ineither the R or S configuration.

More preferred steroid moieties, Z, of the formula VI c in which X═O arefor example those having the radicals of sarsasapogenin, smilagenin,12β-hydroxysmilagenin, rhodeasapogenin, isorhodiasapogenin, samogenin,12β-hydroxysamogenin, markogenin, yonogenin, convallagenin A,convallagenin B, tokorogenin, tigogenin, neotigogenin, gitogenin,agigenin digitogenin, chlorogenin, paniculogenin, (25R)-spirostan-3β,17α,21-triol, allogenin, (25R)-5α-spirostan-2α,3β,5α,6α-tetraol,(24S,25R)-5α-spirostan-2α,3β,5α,6β,24-pentaol, yamogenin diosgenin,yuccagenin, lilagenin, ruscogenin, (25S)-ruscogenin, neopraserigenin,pennogenin, isonuatigenin, cepagenin, 24a-hydroxypennogenin, ophiogenin,sibiricogenin, convallamarogenin, neoruscogenin, hecogenin,neohecogenin, manogenin, sisalagenin and hispigenin.

Preferred steroid moieties, Z, of the formula VI c in which X═NH are forexample those that have the radicals of: solasodine, soladulcidine,tomatidine and 5-dehydrotomatidine.

Preferred steroidal moieties Z of the formula VI c are those having thering structures below; still more preferably having the substitutions asset forth therein.

Further preferred steroidal moieties Z of the formula VI are thosehaving the ring structures below; still more preferably having thesubstitutions as set forth therein.

Preferred steroid moieties VI i to VI xxxii can be derived fromsteroidal glycoside compounds herein, of references of table 2 andadditionally from references (27, 40, 76 to 78 and 86 to 93).

Preferred compounds of the formula I combine preferred Steroid moieties—Z— with preferred saccharide moieties.

In one embodiment compounds of the invention are those of the formulaIII in which the steroid moiety —Z— is selected from group V whichincorporate the further group VIa and in which R⁷, R⁹, R¹⁰, R¹³, R¹⁴,R¹⁶, R¹⁷ and R¹⁹ are H; R¹² is H or —OH; R⁸ , R¹¹ and R¹⁸ are —CH₃; R¹⁵is H or —OH; R²⁰ is —OH or —OCH₃ and R²¹ is 4-hydroxy-3-methylbutanyl,3-methylenebutyl substituted at the 4-position by Glc, 3-methylbutanylsubstituted at the 4-position by Glc, 1-hydroxy-3-methylbutanylsubstituted at the 4-position by Glc or 1-methoxy-3-methylbutanylsubstituted at the 4-position by Glc. It is particularly preferred thatwhen R²¹ is 3-methylenebutyl substituted at the 4-position by Glc thenthe compound of the formula III is compound 25 of table 1a.

Particularly preferred compounds of the formula I are:

Protodioscin, pseudoprotodioscin, protoneodioscin, methylprotodioscin,methylprotoneodioscin, Trigoneoside IVa, glycoside F, Pardarinoside C,Pardarinoside D, dioscin, Balanitin VI, Deltonin, Shatavarin I andShatavarin IV.

Further preferred compounds that are so far un named are Compounds 8,12, 13, 14, 15, 16, 17, 18, 23, 24, 25 and 26 of table 2.

The preferred compounds have the following chemical names:

Protodioscin is[(3β,22α,25R)-26-(β-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl(1→2)-O-[6-deoxy-α-L-mannopyranosyl-(1→4)]-β-D-Glucopyranosidel,pseudoprotodioscin is[(3β,22α,25R)-26-(β-D-glucopyranosyloxy)-furosta-5,20(22)-dien-3-ylO-6-deoxy-α-L-mannopyranosyl(1→2)-O-[6-deoxy-α-L-mannopyranosyl-(1→4)]-β-D-Glucopyranoside],protoneodioscin is[(3β,22α,25S)-26-(β-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl(1→2)-O-[6-deoxy-α-L-mannopyranosyl-(1→4)]-β-D-Glucopyranoside],methylprotodioscin is[(3β,22α,25R)-26-(β-D-glucopyranosyloxy)-22-methoxyfurost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl(1→2)-O-[6-deoxy-α-L-mannopyranosyl-(1→4)]-β-D-Gluco-pyranoside],methylprotoneodioscin is[(3β,22α,25S)-26-(β-D-glucopyranosyloxy)-22-methoxyfurost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl(1→2)-O-[6-deoxy-α-L-mannopyranosyl-(1→4)]-β-D-Glucopyranoside],Trigoneoside IVa is(3β,25S)-26-(β-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside,glycoside F is(3β,25R)-26-(β-D-glucopyranosyloxy)-22-hydroxyfurost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside,Pardarinoside C is(3β,5α,22α,25R)-26-(acetyloxy)-14,17-dihydroxy-22-methoxyfurostan-3-ylO-6-deoxy-α-L-annopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-Glucopyranoside,Pardarinoside D is β-D-glucopyranoside,(3β,5α,22α,25R)-26-(acetyloxy)-17-hydroxy-22-methoxyfurostan-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside,dioscin is [(3β,25R)-spirost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[6-deoxy-α-L-mannopyranosyl-(1→4)]-β-D-glucopyranoside],Balanitin VI is(3β,25S)-spirost-5-en-3-yl-O-α-L-rhamnopyranosyl-(1→2)-O-[β-D-glucopyranosyl-β-D-glucopyranoside,Deltonin is(3β,25R)-spirost-5-en-3-yl-O-α-L-rhamnopyranosyl-(1→2)-O-[β-D-glucopyranosyl-β-D-glucopyranoside,Shatavarin I is(3β,5β,22α,25S)-26-(β-D-glucopyranosyloxy)-22-hydroxyfurostan-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside,Shatavarin IV is (3β,5β,25S)-spirostan-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-β-D-glucopyranoside,

Compound 8 is(3β,25R)-26-(β-D-glucopyranosyloxy)-22-methoxyfurost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-Glucopyranoside,compound 12 is [(3β,12α,25R)-12-hydroxyspirostan-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside],compound 13 is [(25S)-spirost-5-ene-3β27-diol3-O-{6-deoxy-α-L-mannopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside}],compound 14 is [(25R,26R)-26-methoxyspirost-5-en-3β-ol3-O-{6-deoxy-α-L-mannopyranosyl-(1→2)-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside}],compound 15 is[3β,25R,27(S)]-27-(4-carboxy-3-hydroxy-3-methyl-1-oxobutoxy)spirost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside],compound 16 is[3β,25R,27(S)]-27-[(3-hydroxy-5-methoxy-3-methyl-1,5-dioxopentyl)oxy]spirost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside],compound 17 is β-D-Glucopyranoside,(3β,25R,26R)-17-hydroxy-26-methoxyspirost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside,compound 18 is (3β,25R,26R)-26-hydroxyspirost-5-en-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside,compound 23 is 26-O-β-D-glucopyranosylnuatigenin3-O-α-L-rhamnopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranosideCompound 24 is solanidine3-O-α-L-rhamnopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside,compound 25 is (3β,25S)-26-(β-D-glucopyranosyloxy)-22-hydroxyfurost-5,25 (27) dien-3-ylO-6-deoxy-α-L-mannopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside,and compound 26 is solasodine3-O-α-L-rhamnopyranosyl-(1→2)-O-[β-D-glucopyranosyl-(1→4)]-β-D-glucopyranoside

Where any preferred substituent (such as C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl)is said to be composed of from 1 to 6 carbon atoms (ie C₁₋₆) suchsubstituents are more preferred with 1 to 4 carbon atoms (ie C₁₋₄), aremore preferred still with 1 or 2 carbon atoms (ie methyl or ethyl) andare most preferred with only one carbon atom (ie are in the methylform). Likewise where partial substituents such as the C₁₋₆ alkyl groupor C₁₋₆ alkoxy group of C₁₋₆-alkoxy-C₁₋₆-alkyl are said to be composedof from 1 to 6 carbon atoms (ie C₁₋₆) such substituents are,independently one of the other, more preferred with 1 to 4 carbon atoms(ie C₁₋₄), are more preferred still with 1 or 2 carbon atoms (ie methylor ethyl) and are most preferred with only one carbon atom (ie are inthe methyl form).

Alkyl, alkenyl and alykynyl radicals may, where the number of carbons inthe chain permits, be either straight-chain or branched chain. C₁₋₆alkyl radicals may be, for example, methyl, ethyl, n-propyl orisopropyl, n-butyl, isobutyl or tert-butyl, isopentyl, 2,2-dimethylpropyl, n-hexyl, isohexyl and 1,3-dimethylbutyl. C₂₋₆ alkenyl radicalsmay be, for example, allyl, 1-methylprop-2-enyl, 2-methylprop-2-enyl,2-methyl prop-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-but-3-enyl,1-methyl-but-2-enyl, 3-methylbut-2-enyl; where the alkenyl radicalconsists of 2-8 carbon atoms, the possible arrangements include, inaddition to those possible for radicals with 2-6 carbon atoms, thefollowing preferred radicals 5-methyl-hex-5-enyl, 4-methyl-hex-5-enyl,3,4-dimethyl-hex-2-enyl. C₂₋₆ alkynyl may be, for example, propargyl,but-2-ynyl, but-3-ynyl, 1-methylbut-3-ynyl, pent-2-ynyl, pent-3-ynyl,pent-4-ynyl, 4-methyl-pent-2-ynyl. Preferably it is propargyl,1-methylbut-3-ynyl, pent-2-ynyl, pent-4-ynyl or 4-methyl-pent-2-ynyl.

A C₁₋₆ hydroxyalkyl group may, where chemically possible, be either aC₁₋₆ monohydroxyalkyl or a C₁₋₆ dihydroxyalkyl group.

Where moieties may be, in turn, substituted by a saccharide moiety it ispreferred that the bond is through an oxygen to form a group such as:

In the formula I the saccharide moiety A comprises multiple chiralcentres. Thus each of the carbon atoms 1, 2, 3, 4 and 5 can,independently, be in the R or S form. Depending on the form of theanomeric carbon, A can, independently, be in either the alpha or betaanomeric form. For ring A the beta anomeric form is preferred. Thesaccharide moiety A can be in the D or L form; the D form is preferred.Depending on the arrangement around these chiral centres and theidentity of the substituent R₄, the monosaccharide A can take a numberof forms. Thus for example when R⁴ is H, and R¹, R² and R³ are —OH thesaccharide moiety may, for example, be arranged as arabinopyranose,lyxopyranose, ribopyranose or xylopyranose; preferably it isxylopyranose or ribopyranose; more preferably it is xylopyranose.

When R⁴ is —CH₃ and R¹, R² and R³ are —OH the saccharide moiety is a6-deoxy hexopyranose, and may be arranged as 6-deoxyallose,6-deoxyaltrose, 6-deoxygalactose(fucose), 6-deoxyglucose(quinovose),6-deoxygulose, 6-deoxyidose, 6-deoxymannose(rhamnose) or 6-deoxytalosepreferably it is 6-deoxyallose or quinovose; preferably it is quinovose.

Where R⁴ is —CH₂OH and R¹, R² and R³ are —OH the saccharide moiety is ahexopyranose and may be, for example, allose, altrose, galactose,glucose gulose, idose, mannose or talose; preferably it is allose,galactose or glucose, more preferably glucose. When R⁴ is —CH₂OH, R₂ andR₃ are —OH, R₁ is NR⁵R⁶ and R⁵ and R⁶ are H the saccharide may bearranged as a pyranosamine, for example as glucosamine, mannosamine orgalactosamine. When R⁴ is —CH₂OH, R² and R³ are —OH, R¹ is NR⁵R⁶ and R⁵is H and R⁶ is —COCH₃ the saccharide may be arranged as anN-acetylpyranosamine for example N-acetylglucosamine (GlcNAc),N-acetylmannosamine or N-acetylgalactosamine (GalNAc); most preferablyit is GalNAc.

Saccharides include, but are not limited to, monosaccharides,disaccharides, tri saccharides, tetrasaccharides and polysaccharides.Preferably sacchari de moieties are monosaccharides, but may beindependently selected as di- or oligosaccharides.

Monosaccharides include, but are not limited to, tetroses pentoses,hexoses and heptoses; tetroses pentoses and hexoses are preferred.

Tetroses may be for example aldotetroses, such as erithrose and threoseand aldoketoses erithrulose.

Pentoses include, but are not limited to aldopentoses, such asarabinose, lyxose, ribose and xylose and ketopentoses such as ribuloseand xylulose and deoxypentoses such as 2-deoxyribose and 3-deoxyribose.Preferred pentoses are xylose and arabinose. Pentoses may be in thefuranose (eg arabinofuranose, lyxofuranose, ribofuranose andxylofuranose) or the pyranose (eg arabinopyranose, lyxopyranose,ribopyranose and xylopyranose) forms.

Hexoses include, but are not limited to aldohexoses, such as, allose,altrose, galactose, talose, gulose, idose, mannose and glucose(preferred are glucose, mannose, galactose, altrose, allose idose andtalose) and ketokexoses such as fructose, psicose, sorbose and tagatose.

Hexoses may also be deoxy hexoses wherein an —OH group is replaced by an—H group at any position other than the bonded group. 6-deoxyhexoses arefor example 6-deoxyallose, 6-deoxyaltrose, 6-deoxygalactose(fucose),6-deoxyglucose(quinovose), 6-deoxygulose, 6-deoxyidose,6-deoxymannose(rhamnose) or 6-deoxytalose. Deoxyhexoses may also be2-deoxy, 3-deoxy, 4-deoxy and 5-deoxy hexoses. The oxygen may be lackingat more than one position. Examples of deoxyhexoses are—2-deoxy-glucose,2-deoxygalactose, 4-deoxyfucose, 3-deoxygalactose, 2-deoxyglucose,3-deoxyglucose, 4-deoxyglucose. Deoxyaldohexoses are preferred.

Hexoses also include hexosamines such as galactosamine, glucosamine andmannosamine, n-acteyl hexosamines such as N-acetyl-galactosamine,N-acetylmannosamine and N-acetylglucosamine. Preferred hexoses arealdohexoses and deoxy hexoses, particularly preferred hexoses areglucose, galactose, quinovose, fucose and rhamnose.

Hexoses may be in the furanose or pyranose form; preferably in thepyranose form.

Other monosaccharides include uronic acids, for example fructuronicacid, galacturonic acid, iduronic acid, glucuronic acid, guluronic acid,mannuronic acid and tagaturonic acid; sedoheptulose, sialic acid,neuraminic acid, muramic acid, N-acetylneuraminic acid, N-acetylmuramicacid, O-acetylneuraminic acid, and N-glycolylneuraminic acid.

Of hexoses, aldohexoses and deoxyhexoses (particularly deoxyaldohexoses)are preferred; of pentoses, aldopentoses and deoxy-pentoses(particularly deoxyaldopentoses) are preferred.

Pharmaceutically acceptable esters of compounds of the formula 1 are forexample, an ester with an aliphatic or aromatic carboxylic or sulphonicacid. Aliphatic carboxylic acids may be for example of up to 6 carbonatoms, for example a methyl, ethyl, tert-butyl succinyl or malyl.Aromatic carboxylic acids may for example benzoic acid, sulphonic acidsmay be methylsulphonic or p-toluenesulphonic acid, and include esters atany available esterifiable position.

Pharmaceutically acceptable esters further include known compounds inwhich the sugar —OH groups are esterified with an aliphatic carboxylicacid of up to 6 carbon atoms. Also included are known esters at thecarbon 26-position with compounds such as hydroxymethylgluteryric acidor its methyl ester (for example compound 19 and structure VI xxiv).

Pharmaceutically acceptable ethers are, for example, with C₁₋₆hydroxyalkyl compounds which may be formed at any of the available —OHgroups, for example on the saccharide moieties, or steroid moieties byconverting one or more of the —OH groups to alkoxy groups (e.g. 61, 84,85 incorporated herein by reference).

A suitable pharmaceutically-acceptable salt form of the compounds of theformula I is, for example, an acid addition salt with an inorganic ororganic acid, for example hydrochloric, hydrobromic, trifluoroacetic ormaleic acid; or an alkali metal, for example sodium, an alkaline earthmetal, for example calcium, or ammonium, for exampletetra(2-hydroxyethyl)ammonium, salt.

Compounds of the formula I can be extracted from a variety of plantspecies. Examples of sources of compounds of the invention and examplepurification protocols are given in the references of table 2 (which areincorporated herein by reference). Further sources of compounds of theinvention and methods of isolation of such compounds are detailed in(27), particularly tables 2.2, 2.9, 2.10 and 2.11 and appendix 3—andreferences, therein which are incorporated herein by reference.

Many compounds of the invention are hydroxylated steroids. It is knownin the art that such compounds, when exposed to solvent such as alcoholsduring purification or preparation, may be converted to alkoxyderivatives or to other derivatives such as methylketals (which revertto the original compounds upon drying). Particularly furostanolcompounds of the formula VIa, in which the carbon at the at the22-position of the furostanol structure, is substituted by —OH, may beconverted to alkoxy derivatives when exposed to alcohols. Notably suchcompounds may become methoxy derivatives when purified from plantsources using methanol-containing solvents. Alternatively they may beconverted to the corresponding alkoxy by reflux in an appropriateanhydrous alcohol at elevated temperature, for example methanol (36).Such alkoxylated compounds are also compounds of the invention.

Where the compounds of the invention are purified from natural sourcesit is preferred that they are used in isolated form. By isolated ismeant that the compound is at least 1% pure, conveniently it is at least10% pure, more conveniently at least 30% pure, preferably it is at least50% pure more preferably it is at least 80% pure still more preferablyit is at least 90% pure and most preferably it is at least 95% pure.

The purity of the compound is conveniently expressed as a ratio of UVabsorption associated with the compound to UV absorption associated withother material in the sample, conveniently at 205 nm. The purity of thecompound may be measured for example using a chromatography system suchas for example TLC or HPLC such as are described in the referencesherein, particularly in those references relating to the compound inquestion, or in applicants co pending application WO05/060977

Alternatively, compounds of the invention may be synthesised via anumber of routes known to the skilled worker. For example byglycosylation of appropriate aglycones.

A number of suitable aglycones are available commercially, alternativelyan suitable aglycone may be prepared, either by isolation from a naturalsource (27 and references therein), by deglycosylation of a suitableglycosylated compound (for example those compounds disclosed in (27) orherein), or by chemical synthesis from a variety of starting materialthat are readily available.

Methods of synthesising Galβ1-3(6-deoxy)GalNAcα-conjugates are given inPaulsen et al (16) incorporated herein by reference. These methods maybe adapted by the skilled worker in combination with other methodsreferenced herein to synthesize other compounds of the formula I.

The skilled worker will be aware of many sources of spirostanol andfurostanol aglycones suitable for preparing compounds for use in theinvention. For example spirostanol aglycones wherein X═O or X═NH may be,for example, sarsapogenin, smilagenin, 12β-hydroxysmilagenin,Rhodeasapogenin, Isorhodiasapogenin, Samogenin, 12β-hydroxysamogenin,Markogenin, Yonogenin, Convallagenin A, Convallagenin B, Tokorogenin,Tigogenin, Neotigogenin, Gitogenin, Agigenin Digitogenin, Chlorogenin,Paniculogenin, (25R)-Spirostan-3β, 17α21-triol, Allogenin,(25R)-5α-Spirostan-2α,3β3,5α,6α-tetraol,(24S,25R)-5α-Spirostan-2α,3β,5α,6β,24-pentaol, Yamogenin Diosgenin,Yuccagenin, Lilagenin, Ruscogenin, (25S)-Ruscogenin, Neopraserigenin,Pennogenin, Isonuatigenin, Cepagenin, 24a-hydroxypennogenin, Ophiogenin,Sibiricogenin, Convallamarogenin, Neoruscogenin, Hecogenin,Neohecogenin, Manogenin, Sisalagenin, Solasodine, Soladulcidine,Tomatidine and 5-dehydrotomatidine.

Deglycosylation of, for example steroidal glycosides, may be simplycarried out by acid hydrolysis, for example in a 50:50 mix of 2N HCl:dioxane at 100° C. in a sealed tube for 4.5 hrs (36—incorporated hereinby reference).

Methods for the synthesis of a number of steroidal aglycones have beenknown for may years. For example synthesis of diosgenin, yamogenin,kryptogenin and isonarthogenin have been reported by the group of Kessaret al (58-60).

General synthetic routes to a variety of tri saccharide substitutedspirostanol saponins are known (28, 29, 31, 32—incorporated herein byreference). Methods of synthesis of spirostanol saponins having 2,4branched oligosaccharide moieties are also known (33, 28, 34,62—incorporated herein by reference). Methods of synthesis of furostanolsaponins, synthesis of derivatised saponins and interconversion ofspirostanol and furostanol saponins have also been devised (30, 32 to34, 61 to 64—incorporated herein by reference). Furthermore, furostanoland spirostanol saponins can be inter converted using a β-glucosidaseand pseudosaponins maybe cyclised to form the spirostanol derivative(63, 65—incorporated herein by reference).

Combinatorial approaches to saponin synthesis have also been reported(66, 30—incorporated herein by reference).

These references also provide information and further references onderivatisation of saccharide hydroxyl and hydroxyalkyl groups.

As used herein the term aglycone refers to steroidal glycosides whereinthe saccharide moieties are not present (e.g. page 29 line 18). Thecompounds may have other substituents at the position originallyoccupied by the saccharide moiety. Particularly aglycones that arefurostanol saponins when not glycosylated may be in the ring closedstate as the equivalent spirostanol compounds. Steroidal glycosides arecompounds having a steroid or substituted steroid core, to which isattached one or more saccharide moieties. A steroidal sapogenin is theaglycone of a steroidal saponin. A steroidal saponin is a naturallyderived steroidal glycoside.

An anti cell adhesion agent is an agent that reduces the adhesion ofcells to a substrate such as platelets or the lining of blood vessels orother tissues, an anti cell-cell interaction agent is an agent thatreduces the interaction between cells. An anti cellular extravasationagent is an agent that reduces the passage of cells from the bloodstream through the walls of blood vessels.

The term “treating”, as used herein, includes treating as prophylaxis ortreatment of a current or remitting illness.

For the avoidance of doubt the term C₁₋₆ acyl is —CO—C₁₋₅-alkyl.

In a second aspect of the invention is provided the use of compounds ofthe formula I in the manufacture of a medicament for the treatment of acondition associated with detrimental activity, particularly raisedactivity, of the enzyme core 2 GlcNAc-T.

In a third aspect of the invention is provided the use of a compound offormula I as an anti cell adhesion agent, an anti cell-cell interactionagent or an anti cellular extravasation agent.

In a fourth aspect of the invention is provided a pharmaceuticalcomposition comprising compound of the formula I.

Medicaments of the invention comprising compounds of the formula I willtypically be prepared in a sterile and pyrogen free form. They can beadministered by oral or parenteral routes, including intravenous,intramuscular, intraperitoneal, subcutaneous, transdermal, airway(aerosol), rectal, vaginal and topical (including buccal and sublingual)administration.

The medicament may be made up in liquid form in which case it willtypically, in addition to the compound of the formula I, comprise apharmaceutically acceptable diluent or it may be made up in solid form.

For oral administration, the compounds of the invention will generallybe provided in the form of tablets or capsules, as a powder or granules,or as an aqueous solution or suspension.

Tablets for oral use may include the active ingredients mixed withpharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavouring agents, colouring agents and preservatives. Examplesof suitable inert diluents include sodium and calcium carbonate, sodiumand calcium phosphate, and lactose, while corn starch and alginic acidare examples of suitable disintegrating agents. Binding agents include,for example starch and gelatine, while the lubricating agent, ifpresent, may for example, be magnesium stearate, stearic acid or talc.If desired, the tablets may be coated with an enteric coating material,such as glyceryl mono stearate or glyceryl distearate, to delayabsorption in the gastrointestinal tract. Capsules for oral use includehard gelatine capsules in which the active ingredient is mixed with asolid diluent, and soft gelatine capsules wherein the active ingredientsis mixed with water or an oil such as peanut oil, liquid paraffin orolive oil

Formulations for rectal administration may for example be presented as asuppository with a suitable base comprising, for example, cocoa butteror a salicylate.

Formulations suitable for vaginal administration may for example bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations containing in addition to the active ingredient suchcarriers as are known in the art to be appropriate.

In preparations for intramuscular, intraperitoneal, subcutaneous andintravenous use, the compounds of the invention will typically beprovided in a pharmaceutically acceptable diluent to provide sterilesolutions, emulsions, liposome formulations or suspensions. Typicallythe preparation will be buffered to an appropriate pH and isotonicity.For example suitable diluents include Ringer's solution and isotonicsodium chloride. Aqueous suspensions according to the invention mayinclude suspending agents such as cellulose derivatives, sodiumalginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agentsuch as lecithin. Suitable preservatives include ethyl and n-propylp-hydroxybenzoate.

The isolated Core 2 GlcNAc-T inhibitors of the invention may also beincorporated into a food or beverage product.

In general a suitable dose of Core 2 GlcNAc-T inhibitor will be in therange of 100 ng to 10 mg per kilogram body weight of the recipient perday, preferably in the range of 1 μg to 5.0 mg/kg/d. Typically thedesired dose is presented once daily or several times a day in subdoses. These sub-doses may be administered in unit dosage forms, forexample, containing 1 μg to 1500 mg, preferably 40 μg to 1000 mg, andmost preferably 50 μg to 700 mg of active ingredient per unit dosageform.

In the shorthand annotation:

used in structures herein Glc is glucose and Rha is rhamnose. Theannotation 2,3 and 2,4 denote the position of attachment of thesaccharides to the central monosaccharide.

The shorthand notation

used in structures herein denotes the structure:

The present invention will now be described further by reference to thefollowing non-limiting Examples, Schemes and Figures. Furtherembodiments falling within the scope of the claim will- occur to thoseskilled in the art in the light of these.

EXAMPLES

TABLE 1 Example compounds of the invention. Table 1a

25 Bond Bond Compound Q A¹ A² A³ A⁴ A⁵ A⁶ A⁷ R/S a b  1 4- Me H H Glc OHH H R Double Single Rha  2 4- Me H H Glc Absent H H R Double Double Rha 3 4- Me H H Glc OH H H S Double Single Rha  4 4- Me H H Glc OMe H H RDouble Single Rha  5 4- Me H H Glc OMe H H S Double Single Rha  6 4- MeH H Glc OH H H S Double Single Glc  7 4- Me H H Glc OH H H R DoubleSingle Glc  8 4- Me H H Glc OMe H H R Double Single Glc  9 4- Me H OH—O•CO•CH₃ OMe OH H R Single Single Glc 10 4- Me H OH —O•CO•CH₃ OMe H H RSingle Single Glc 21 4- Me H H Glc OH H H S Single Single Glc 25 4- ═CH₂H H Glc OH H H — Double Single Glc 27*** 3- Me H H Glc OH H H R DoubleSingle Glc Table 1b

Comp. Q A₁ A₂ A₃ A₄ A₅ A₆ 25R/S Bond a 11 4-Rha Me H H H H H R Double 124-Glc Me H H H OH H R Single 13 4-Glc —CH₂OH H H H H H S Double 14 4-GlcMe H H H H OMe R Double 15 4-Glc * H H H H H R Double 16 4-Glc ** H H HH H R Double 17 4-Glc Me H OH H H OMe R Double 18 4-Glc Me H H H H OH RDouble 19 4-Glc Me H H H H H S Double 20 4-Glc Me H H H H H R Double 224-Glc Me H H H H H S Single Table 1c Further example compounds of theinvention Compound Structure 23

24

26

***comparative compound Substituent “*” =

Substituent “**” =

TABLE 2 Key to example compounds of the invention and references ExampleCompound references Compound name 1 36 Protodioscin 2 37Pseudoprotodioscin 3 36 Protoneodioscin 4 36 Methylprotodioscin 5 36Methylprotoneodioscin 6 17 Trigoneoside IVa 7 22, 17 Glycoside F,protodeltonin, deltoside, 8 42 No name 9 19 Pardarinoside C 10 19Pardarinoside D 11 39 Dioscin 12 38 Not named 13 20, 40, 41, 42 Notnamed 14 40, 42 Not named 15 40, 41, 20, 21 Not named 16 41, 20 Notnamed 17 42 Not named 18 43 Not named 19 26, 42, 25 Balanitin VI 20 24,71 Deltonin 21 18, 23 Shatavarin I 22 18, 23 Shatavarin IV 23 20 Notnamed 24 21 Not named 25 WOO5060977 Not named 26 20 Not named 27 36Protogracillin*** ***comparative example compound.

Example 1 Biological Activity of Compounds

All compounds used herein were supplied by Chromadex Inc. 2952 S.Daimler Street Santa Ana Calif. 92705. Compounds used were at least 88%pure

TABLE 4 Purity of compounds used Compound Number Purity Protodioscin 193.3% Pseudoprotodioscin 2 88.6% Dioscin 11 90.8% Trigoneoside IVa 6  89% Glycoside F 7 80.3% Shatavarin I 21  >95% ***Protogracillin 2698.8% Purity was determined by HPLC using UV absorption at 205 nm1a. Cell Culture

The human leukocytic cell-line (U937) was cultured in RPMI supplementedwith 10% foetal calf serum, 2 mM glutamine, 100 IU/ml penicillin and 100μg/ml streptomycin.

1b. Assay of Core 2 GlcNAc-T Activity

(i). Glucose induction of Core 2 GlcNAc-T leukocytes (U937 cells) wereexposed to normal glucose (5.8 mM) or high glucose (15 mM) for 24 hoursat 37° C. After incubation, the cells maybe lysed and frozen at −20° C.until used for the measurement of core 2 GlcNAc-T or used immediately.

(ii). TNF-α induction of core 2 GlcNAc-T. Human leukocytes(U937 cells)were exposed to human recombinant TNF-alpha (8 pg/ml) in the presenceand absence of test compounds After 24 h incubation, the activity ofcore 2 GlcNAc-T was measured, and expressed as pmoles/h/mg protein

(iii). Cell free assay of core 2 GlcNAc-T in cell free assays of core 2GlcNAc-T Heart lysates from either from TNF-alpha over expressingtransgenic mice (female, B6.SJL-Tg (TNF) supplied by Taconic-M+B,Bomholtveg 10, 8680 Ry, Denmark) or from BB rats (Festing 1979) wasexposed to various concentrations of test compound for 1 h at 37° C.Activity of core 2 GlcNAc-T was measured, and expressed as pmoles/h/mgprotein.

1c. Measurement of Core 2 GlcNAc-T Activity

To measure core 2 GlcNAc-T activity, leukocytes were washed in PES,frozen and lysed in 0.9% Triton X-100 at 0° C. The activity of core 2GlcNAc-T was measured as described below. Cell free assays are preformedby substituting heart lysates for cell lysates.

The reaction was performed in a reaction mixture containing 50 mM2(N-morpholino)ethanesulfonic acid (MES, Sigma, Dorset, UK), pH 7.0, 1mM UDP-6 ['H]-N-acetylglucosamine (16,000 dpm/nmol, NEN Life ScienceProducts, Hounslow, UK), 0.1 M GlcNAc (Sigma, Dorset, Okla.), 1 mMGalβ1-3GalNAcα-p-nitrophenol (Sigma, Dorset, UK) as substrate, and 16 μlof lysate (100-200 μg protein) for a final volume of 32 μl. Afterincubating the mixture for 1 hour at 37° C., the reaction was terminatedwith 1 ml of ice-cold distilled water and processed on a C18 Sep-Pakcolumn (Waters-Millipore, Watford, UK). After washing the column with 20ml of distilled water, the product was eluted with 5 ml of methanol. Theradioactivity of the samples was counted in a liquid scintillationβ-counter (LKB-Wallac, London, UK). Endogenous activity of core 2GlcNAc-T was measured in the absence of the added acceptor. The specificactivity was expressed as pmoles/h/mg of cell protein. In each case, theprotein concentration was determined with BioRad protein assay (BioRad,Hertfordshire, UK). Results are shown in table 5.

TABLE 5 Approximate Ic₅₀ values (nM) for example compounds Cell freeCell based Compound Number assay assay Protodioscin 1  20** aPseudoprotodioscin 2 35* 50 Dioscin 11 40* 75 Trigoneoside IVa 6   0.9*75 Glycoside F 7  5** b Shatavarin I 21  1* 0.75 Shatavarin IV 22 c** †***Protogracillin 26  3* 0.25 *Cell free assays were carried out onheart lysates of TNF-α mice as described above. **Cell free assays werecarried out on heart lysates of BB rats as described above. a 33%inhibition at 20 nM b 100% inhibition at 22 nM n BB rat heart lysate c89% inhibition at 22 nM in BB rat heart lysate † no activity detected at22.5 nM ***comparative compound

Compound C (at 20 ng/ml) was found to inhibit Core 2 GlcNAc-Tapproximately 98.5% compared to controls, in TNF-□ treated Humanleukocytes (U937 cells). The sample of compound C was approximately82.5% pure by HPLC at 205 nM

The approximate IC₅₀ of Trigoneoside IVa was found to be between 0.25 nMand 0.9 nM in cell free systems. Further analysis of a sample preparedaccording to applicants co pending WO05/060977 indicates that itcontains approximately 7.5% protodioscin and 9% Trigonelloside C (17).

The IC₅₀ of Glycoside F was found to be approximately 5 nM. Furtheranalysis of the preparation indicates that it contains a small amount ofTrigonelloside C.

The IC₅₀ of Protodioscin (93.3% pure) produced as described inapplicants co pending WO05/060977 was found to be approximately 20 nM.The sample contained 1.5% Trigoneoside IVa. A sample prepared fromTribulus terrestris (Chromodex Inc. 2952 S. Daimler Street Santa AnaCalif. 92705), which was 97% pure, and had an NMR spectrum consistentwith protodioscin, appeared to demonstrate no activity at concentrationsof 50 μM. Thus Trigoneoside IVa activity could account for at least someof the activity seen in the protodioscin sample prepared as perWO05/060977.

Trigonelloside C is similar to Protodioscin but is the opposite isomerat carbon 25. A preparation of this compound according to co pendingWO05/060977 was 98.2% pure and contained no measurable quantity of otherCore 2 GlcNAc-T inhibitors. A preparation of Trigonelloside C preparedaccording to WO05/060977 inhibited Core 2 GlcNAc-T 69% at 2.5 nM.

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1-27. (canceled)
 28. A food or beverage product into which has beenincorporated a compound of the formula (I) isolated to at least 1%purity

wherein R¹ is H, —OH, C₁₋₆ alkoxy, —NR⁵R⁶, or Sac 1; R² is H, —OH, C₁₋₆alkoxy or Sac 2; R³ is H, —OH, C₁₋₆ alkoxy or Sac 3; R⁴ is H, C₁₋₆alkyl, C₁₋₆ hydroxyalkyl or C₁₋₆-alkoxy-C₁₋₆-alkyl; R⁵ is H, C₁₋₆ alkylor C₁₋₆ acyl; R⁶ is H, C₁₋₆ alkyl or C₁₋₆ acyl; Sac 1 Sac 2 and Sac 3are independently selected saccharide moieties; and Z is a steroidmoiety; or a pharmaceutically acceptable salt, ether or ester formthereof.
 29. A food or beverage product according to claim 28 in whichR¹ is —OH, or Sac
 1. 30. A food or beverage product according to claim28 in which Sac 1 is selected from a pentose, a deoxy-aldohexose and analdohexose.
 31. A food or beverage product according to claim 28 inwhich R² is —OH.
 32. A food or beverage product according to claim 28 inwhich R³ is Sac
 3. 33. A food or beverage product according to claim 28in which Sac 3 is selected from a pentose, a deoxy-aldohexose and analdohexose.
 34. A food or beverage product according to claim 28 inwhich Sac 3 is selected from a pentose, and an aldohexose.
 35. A food orbeverage product according to claim 28 in which Sac 3 is an aldohexose.36. A food or beverage product according to claim 28 in which Sac 3 isglucose.
 37. A food or beverage product according to claim 28 in whichR¹ is —OH, C₁₋₆ alkoxy, —NR⁵R⁶; R² is Sac 2 and R³ is —OH.
 38. A food orbeverage product according to claim 37 in which R¹ —NR⁵R⁶.
 39. A food orbeverage product according to claim 28 in which R⁴ is H, —CH₂OH or —CH₃.40. A food or beverage product according to claim 28 in which R⁵ is H or—CH₃.
 41. A food or beverage product according to claim 28 in which R⁶is H or —COCH₃.
 42. A food or beverage product according to claim 28 inwhich the steroid group, Z, is of the formula IV:

wherein: R⁷ and R¹⁴ are independently selected from H and —OH; R⁸ isC₁₋₆ alkyl; R⁹, R¹¹, R¹⁶ are independently selected from H and C₁₋₆alkyl; R¹⁰ is H or —OH or the H normally also present is absent and R¹⁰is ═O; R¹² is H, —OH or C₁₋₆acyl or a group selected from VII a or VIIb;

R¹³ is H; R¹⁵ is H, —OH or C₁₋₆ alkyl or R¹³ and R¹⁵ taken together forma —CH₂—CH₂— group; R¹⁷ is H, C₁₋₆ alkyl or C₁₋₆ hydroxyalkyl; R²² is Hor —OH; R²⁹ is C₁₋₆ alkyl; R³⁰ is C₁₋₆ hydroxyalkyl; R³¹ is C₁₋₆ alkyl,C₁₋₆ hydroxyalkyl or C₁₋₆ alkyl substituted by Sac 5; R³² is C₁₋₈ alkyl,C₂₋₈ alkenyl or C₂₋₈ alkynyl; and

represents a bond that is either double or single.
 43. A food orbeverage product according to claim 42 in which the steroid moiety Zincorporates a further group selected from the groups consisting ofgroups VI (a) to VI (e):

wherein: R¹⁸, R²³, R²⁷ and R³³ are independently selected from C₁₋₆alkyl; R¹⁹ and R²⁴ are independently selected from H and —OH; R²⁰ is H,—OH or C₁₋₆ alkoxy or R¹⁹ and R²⁰ taken together represent the secondbond of a double bond joining adjacent carbon atoms; R²¹ is C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl or a C₁₋₆ alkyl or C₂₋₆ alkenyl groupsubstituted by one or more groups selected from the group consisting of—OH, C₁₋₆ alkoxy and Sac 4; R²⁵ is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl or═CH₂; R²⁶ is —OH; R²⁸ is C₁₋₆ alkyl, C₂₋₆ alkenyl or C₂₋₆ alkynyl; R³⁴is C₁₋₆ hydroxyalkyl or C₁₋₆ alkyl substituted by Sac 6; R³⁵ is C₁₋₆alkyl; Sac 4, Sac 5 and Sac 6 are independently selected saccharides; Xis either O or NH.
 44. A food or beverage product according to claim 43in which R²¹ is C₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkynyl or a C₁₋₆ alkylgroup substituted by one or more groups selected from the groupconsisting of —OH, C₁₋₆ alkoxy and Sac
 4. 45. A food or beverage productaccording to claim 43 in which R²¹ is C₂₋₆ alkenyl, or a C₁₋₆ alkylgroup substituted by one or more groups selected from the groupconsisting of —OH, C₁₋₆ alkoxy and Sac
 4. 46. A method according toclaim 42 in which R²¹ is C₂₋₆ alkenyl or a C₁₋₆ alkyl group substitutedby one or more groups selected from the group consisting of —OH, —OCH₃and Sac
 4. 47. A food or beverage product according to claim 42 in whichSac 4 is glucose.
 48. A food or beverage product according to claim 42in which R³¹ is —CH₃ or —CH₂-Sac
 5. 49. A food or beverage productaccording to claim 42 in which Sac 5 is glucose.
 50. A food or beverageproduct according to claim 42 in which R³⁴ is —CH₂-Sac-6.
 51. A food orbeverage product according to claim 42 in which Sac 6 is glucose.
 52. Afood or beverage product according to claim 42 in which X is O.
 53. Amethod of treating a subject in need of therapy for a conditioninvolving detrimental activity of the enzyme core 2 GlcNAc-T comprisingadministering to the subject a food or beverage product into which hasbeen incorporated an isolated compound of the formula (I) according toclaim
 28. 54. A method according to claim 53 in which the condition tobe treated is selected from the group consisting of vascular diseases,autoimmune and inflammatory conditions.
 55. A method according to claim54 in which the condition to be treated is selected from the groupconsisting of: multiple sclerosis, myopathy, retinopathy, nephropathy,atherosclerosis, asthma, rheumatoid arthritis, inflammatory boweldisease, transplant rejection, ischemia reperfusion injury, restenosis,ileitis, Crohn's disease, thrombosis, cholitis, lupus, frost biteinjury, acute leukocyte mediated lung injury, traumatic shock, septicshock, nephritis, psoriasis, cholicytitis, cirrhosis, diverticulitis,fulminant hepatitis, gastritis, gastric and duodenal ulcers, hepatorenalsyndrome, irritable bowel syndrome, jaundice, pancreatitis, ulcerativecholitis, Wiskott-Aldrich syndrome T-cell activation, AIDS, infectionwith viruses, bacteria, protozoa and parasites adapted to use core 2derived glycans, cancer and cancer metastasis.